Shaw Julia C, Berry Mary J, Dyson Rebecca M, Crombie Gabrielle K, Hirst Jonathan J, Palliser Hannah K
School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, NSW, Australia.
Mothers and Babies Research Centre, Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW, Australia.
Front Physiol. 2019 May 15;10:599. doi: 10.3389/fphys.2019.00599. eCollection 2019.
Children born preterm are at an increased risk of developing cognitive problems and neuro-behavioral disorders such as attention deficit hyperactivity disorder (ADHD) and anxiety. Whilst neonates born at all gestational ages, even at term, can experience poor cognitive outcomes due to birth-complications such as birth asphyxia, it is becoming widely known that children born preterm in particular are at significant risk for learning difficulties with an increased utilization of special education resources, when compared to their healthy term-born peers. Additionally, those born preterm have evidence of altered cerebral myelination with reductions in white matter volumes of the frontal cortex, hippocampus and cerebellum evident on magnetic resonance imaging (MRI). This disruption to myelination may underlie some of the pathophysiology of preterm-associated brain injury. Compared to a fetus of the same post-conceptional age, the preterm newborn loses access to factors that support and promote healthy brain development. Furthermore, the preterm environment is hostile to the developing brain with a myriad of environmental, biochemical and excitotoxic stressors. Allopregnanolone is a key neuroprotective fetal neurosteroid which has promyelinating effects in the developing brain. Preterm birth leads to an abrupt loss of the protective effects of allopregnanolone, with a dramatic drop in allopregnanolone concentrations in the preterm neonatal brain compared to the fetal brain. This occurs in conjunction with reduced myelination of the hippocampus, subcortical white matter and cerebellum; thus, damage to neurons, astrocytes and especially oligodendrocytes of the developing nervous system can occur in the vulnerable developmental window prior to term as a consequence reduced allopregnanolone. In an effort to prevent preterm-associated brain injury a number of therapies have been considered, but to date, other than antenatal magnesium sulfate and corticosteroid therapy, none have become part of standard clinical care for vulnerable infants. Therefore, there remains an urgent need for improved therapeutic options to prevent brain injury in preterm neonates. The actions of the placentally derived neurosteroid allopregnanolone on GABA receptor signaling has a major role in late gestation neurodevelopment. The early loss of this intrauterine neurotrophic support following preterm birth may be pivotal to development of neurodevelopmental morbidity. Thus, restoring the neurosteroid environment for preterm neonates may represent a new and clinically feasible treatment option for promoting better trajectories of myelination and brain development, and therefore reducing neurodevelopmental disorders in children born preterm.
早产儿童出现认知问题和神经行为障碍（如注意力缺陷多动障碍（ADHD）和焦虑症）的风险增加。虽然所有孕周出生的新生儿，即使是足月儿，也可能因出生窒息等出生并发症而出现不良认知结果，但众所周知，与健康的足月儿相比，早产儿童尤其有学习困难的重大风险，且特殊教育资源的利用率更高。此外，早产儿童有脑髓鞘形成改变的证据，磁共振成像（MRI）显示额叶皮质、海马体和小脑的白质体积减少。这种髓鞘形成的破坏可能是早产相关脑损伤某些病理生理学的基础。与相同孕龄的胎儿相比，早产新生儿无法获得支持和促进健康脑发育的因素。此外，早产环境对发育中的大脑不利，存在大量环境、生化和兴奋性毒性应激源。别孕烯醇酮是一种关键的神经保护胎儿神经甾体，在发育中的大脑中具有促髓鞘形成作用。早产导致别孕烯醇酮的保护作用突然丧失，与胎儿脑相比，早产新生儿脑中别孕烯醇酮浓度急剧下降。这与海马体、皮质下白质和小脑的髓鞘形成减少同时发生；因此，在足月前的脆弱发育窗口期间，由于别孕烯醇酮减少，发育中的神经系统的神经元、星形胶质细胞，尤其是少突胶质细胞可能会受到损伤。为了预防早产相关脑损伤，人们考虑了多种治疗方法，但迄今为止，除了产前硫酸镁和皮质类固醇治疗外，没有一种方法成为脆弱婴儿标准临床护理的一部分。因此，迫切需要改进治疗方案以预防早产新生儿的脑损伤。胎盘衍生的神经甾体别孕烯醇酮对GABA受体信号传导的作用在妊娠后期神经发育中起主要作用。早产后宫内这种神经营养支持的早期丧失可能是神经发育疾病发生的关键。因此，恢复早产新生儿的神经甾体环境可能代表一种新的临床可行治疗选择，以促进更好的髓鞘形成和脑发育轨迹，从而减少早产儿童的神经发育障碍。
